Gastroenterology

Gastroenterology

Volume 122, Issue 7, June 2002, Pages 1800-1807
Gastroenterology

Clinical Research
Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus☆,☆☆,★

https://doi.org/10.1053/gast.2002.33580Get rights and content

Abstract

Background & Aims: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of cancer in the digestive tract. Cyclooxygenase (COX) is the best-known target of NSAIDs, and expression of the COX-2 isoform is elevated in esophageal carcinomas but its clinical significance remains unclear. We examined COX-2 expression in esophageal adenocarcinomas and its relation to clinicopathologic parameters. Methods: Tumor sections from 145 consecutive patients undergoing intentionally curative surgery for an adenocarcinoma arising from a Barrett's esophagus were immunohistochemically stained using a COX-2–specific anti-human monoclonal antibody. The specimens were scored based on the intensity and extent of COX-2 immunopositivity. Results: COX-2 immunoreactivity was negative to weak in 21% (COX-2 low) and moderate to strong in 79% (COX-2 high) of the carcinomas. Patients with high COX-2 expression were more likely to develop distant metastases (P = 0.02) and local recurrences (P = 0.05), and survival was significantly reduced (P = 0.002, log-rank test) among patients with high COX-2 expression when compared with the COX-2 low group. Five-year survival rates were 35% (95% confidence interval [CI], 23–47) and 72% (95% CI, 53–90) in COX-2 high and COX-2 low categories, respectively. Furthermore, expression of COX-2 was recognized as an independent prognostic factor by multivariate analysis (relative risk, 3.5; 95% CI, 1.6–7.9). Conclusions: Elevated expression of COX-2 protein is associated with significantly reduced survival of patients undergoing surgery for esophageal adenocarcinoma. These findings support the effort to initiate clinical studies to investigate the effect of COX-2 inhibitors as a novel (adjuvant) chemotherapeutic modality for the treatment of adenocarcinoma arising from Barrett's esophagus.

GASTROENTEROLOGY 2002;122:1800-1807

Section snippets

Patients

Between January 1, 1993, and December 31, 2000, 306 patients underwent esophageal resection for adenocarcinoma of the esophagus or gastroesophageal junction with curative intent (i.e., locally resectable disease without distant metastases) at the Department of Surgery of the Academic Medical Center, Amsterdam, The Netherlands. Preoperative workup included endoscopy with biopsy, external ultrasonography of the abdomen and neck, radiography of the chest, esophageal endosonography, and indirect

Formation and demographic characteristics of the cohort

Of the original 306 esophageal resections for an adenocarcinoma, 151 patients had a Barrett's carcinoma. Six specimens were excluded during the immunohistochemical analyses, so 145 patients were included into this study (see Patients and Methods for details). There were 120 men (82.8%) and 25 women (17.2%) with a mean age of 65.7 years (range, 34.8–85.2 years).

Immunohistochemical expression of COX-2

COX-2 immunoreactivity was detected in 143 of the 145 esophageal adenocarcinoma specimens (98.6%). Moderate to strong staining with a

Discussion

Our data indicate that elevated expression of COX-2 is associated with reduced survival in patients undergoing surgery for adenocarcinoma of the esophagus. Patients with tumors with high COX-2 expression had a more aggressive course of their disease, because they were more likely to develop distant metastases and local recurrences, leading to higher mortality rates. This higher mortality could not be explained by a more advanced disease stage at the time of surgery. Multivariate analyses

Acknowledgements

The authors thank Eric Caspers, Folkert Morsink, and Alex Musler from the Department of Pathology at the Academic Medical Center and Elina Laitinen from the Helsinki University Central Hospital for excellent technical assistance as well as Dr. Pentti Sipponen for critical reading of the manuscript.

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    ☆

    Address requests for reprints to: Ari Ristimäki, M.D., Ph.D., Molecular and Cancer Biology Research Program, Biomedicum Helsinki, Room B512b, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 Helsinki, Finland. e-mail: [email protected]; fax: (358) 9-191-26700.

    ☆☆

    Supported by travel grants from the Netherlands Organization for Scientific Research (NWO-MW) and the Academy of Finland (to C.J.B., B.P.V.R., and A.R.) as well as the Academy of Finland, the Finnish Cancer Foundation, Finska Läkaresällskapet, and Helsinki University Central Hospital Research Funds (to A.R. and C.H.).

    ★

    C.J.B. and B.P.V.R. contributed equally to this work and appear in alphabetical order.

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    Copyright © 2002 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.